hTERT peptide vaccines
Human telomerase reverse transcriptase (hTERT) is an overexpressed tumor-associated antigen (TAA) in over 85% of tumors, including tumors of hematopoietic tissue and solid tumors [1]. hTERT expression is required for tumor immortality, especially in cancer stem cells, and is one of the crucial targets for cancer immunotherapy [2] . Its expression is absent in most normal tissues and only present at low levels in hematopoietic stem cells, basal keratinocytes, and human germline cells. Up to date, several trials with hTERT-based peptide vaccines have been conducted and showed no toxicity to normal tissues after vaccination. Furthermore, confirmation of typical bone marrow functionality was obtained.
GV1001
GV1001, a 16-amino acid peptide of hTERT, residues 611–626 fragment (EAR PAL LTS RLR FIP K) [3]，has emerged as a promising immunotherapeutic agent with potential applications across various cancer types, stimulating robust CD4+ T cell responses in up to 80% of vaccinated patients [4]. Moreover, GV1001 harbors putative HLA-Class I epitopes, suggesting the possibility of eliciting combined CD4+ and CD8+ T-cell responses, crucial for tumor eradication and long-term immune memory [3].
Clinical trials in pancreatic adenocarcinoma [5], non-small cell lung cancer (NSCLC) [6, 7] and malignant melanoma [4, 8] cancers have demonstrated the safety and efficacy of the GV1001 vaccination. In pancreatic cancer, intradermal administration of GV1001 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) induced immune responses in a significant proportion of patients, correlating with improved survival rates [5]. Similarly, in NSCLC patients, GV1001 vaccination elicited durable T cell responses, with some patients achieving complete remissions and prolonged survival, supporting the combination of chemoradiotherapy with vaccination for further exploration.
However, not all trials yield positive outcomes. In a phase III trial for pancreatic cancer (TeloVac), GV1001 vaccination in combination with chemotherapy did not improve overall survival compared to chemotherapy alone, highlighting the need for new strategies to enhance immune response during chemotherapy [9]. Additionally, GV1001 vaccination in cutaneous T cell lymphoma (CTCL) patients failed to induce objective clinical responses, emphasizing the importance of refining vaccine strategies for specific cancer types [10].
Despite these challenges, GV1001 has shown promise in various settings. In metastatic breast cancer, GV1001 combined with cytotoxic chemotherapy demonstrated disease control and overall response rates, suggesting potential benefit across different breast cancer subtypes [11]. In benign prostatic hyperplasia (BPH) patients, GV1001 showed efficacy in improving symptoms and reducing prostate volume, indicating potential as an alternative therapy [12].
GV1001 represents a versatile immunotherapeutic approach with the ability to induce robust immune responses and improve clinical outcomes in certain cancer types. Further research is warranted to optimize its efficacy, refine vaccination strategies, and explore its potential in combination with other treatment modalities to maximize therapeutic benefits across a broader spectrum of cancers.
GV1001 CPP functions
Cell-penetrating peptides (CPPs) are instrumental in facilitating the transport of molecular cargo across cell membranes. GV1001, initially devised as a cancer vaccine, exhibits unique CPP properties, facilitating the intracellular delivery of large molecules via extracellular heat shock proteins 90 and 70 (eHSP90 and eHSP70). The interactions between eHSPs and GV1001 suggest broader biological implications beyond its initial anticancer purpose [13].
Examination of GV1001 uncovers its diverse functions, including its role as a ligand for the gonadotropin-releasing hormone receptor (GnRHR), which triggers specific activation of the Gαs/cAMP pathway in prostate cancer (PCa) cells, ultimately hindering metastasis. Moreover, GV1001 demonstrates potential therapeutic effects in benign prostatic hyperplasia and castration-resistant prostate cancer by modulating various pathways, including AKT/NF-kB/VEGF and VEGF-A/VEGFR-2, thereby suppressing tumor growth and angiogenesis [14-18].
GV1001 also exhibits promising outcomes in pancreatic cancer, renal cell carcinoma (RCC) [19], and mitigating ototoxicity while protecting against hearing loss [20, 21]. Additionally, GV1001 shows anti-inflammatory effects by reducing pro-inflammatory cytokine production and presents multifaceted benefits in periodontitis, rheumatoid arthritis, and myocardial ischemia-reperfusion injury [22-25]. Its potential cardioprotective, neuroprotective, and anticancer properties highlight GV1001 as a versatile peptide with therapeutic potential across various diseases. [26-31]
Vx-001
Vx-001, an anti-tumor vaccine containing the 9-mer cryptic TERT (572) peptide and its optimized variant TERT (572Y), has shown promising results in various studies evaluating its safety, efficacy, and immunogenicity in advanced cancer patients. Initial phase I trials demonstrated the safety and efficacy of the optimized cryptic peptide TERT (572Y) in refractory tumor patients [32]. Further optimization studies comparing TERT (572Y) and TERT572 peptides suggested an effective immunotherapy schedule, eliciting higher T cell responses with optimal results achieved by administering TERT (572Y) followed by TERT572 peptides. [33]
In subsequent studies, Vx-001 demonstrated non-toxicity and high immunogenicity in chemo-resistant solid tumor patients, leading to specific T-cell responses and significant survival benefits, even in patients with disease progression at entry [34]. Expanded phase II trials in patients with advanced solid tumors, particularly in HLA-A*0201-positive patients, revealed a correlation between TERT-specific immune response and improved clinical outcomes, including disease control rate, progression-free survival, and overall survival [35].
Specifically in HLA-A*0201-positive NSCLC patients, Vx-001 showed promising results with a disease control rate of 28%, significantly higher rates in non-squamous histology, and median progression-free survival and overall survival of 3.8 and 19.8 months, respectively. Patients exhibiting immune responses had significantly prolonged overall survival, indicating the potential clinical benefits of Vx-001 in this subgroup [36].
While a phase 2b trial with HLA-A*201-positive NSCLC patients did not meet its primary endpoint of overall survival improvement, patients with a lasting TERT-specific immune response showed significantly longer overall survival, suggesting potential benefits for specific subgroups warranting further investigation [37]. Additionally, other strategies targeting hTERT have been explored, such as the construction of a recombinant human telomerase reverse transcriptase (hTERT)-human IL-18 (hIL18) fusion protein, demonstrating strong telomerase activity and enhanced anti-apoptotic effects, as well as the assessment of hTERT-derived peptide vaccines in hepatocellular carcinoma patients, which induced hTERT-specific immunity and prevented HCC recurrence in a significant proportion of patients [38, 39].
These findings collectively underscore the potential of TERT-targeting immunotherapies, including Vx-001 and related approaches, in the treatment of advanced cancers, with implications for improving clinical outcomes and addressing unmet medical needs in various patient populations.
UV1 vaccine
The UV1 vaccine, developed by Ultimovacs ASA, is designed to achieve broad population coverage in cancer immunotherapy. It comprises three synthetic long peptides containing multiple epitopes, including a 30-mer and two 15-mers, selected based on immunological analyses of blood from long-term cancer survivors treated with a first-generation hTERT vaccine (GV1001). The UV1 peptides incorporate hTERT epitopes most frequently recognized in GV1001-vaccinated patients, indicating epitope spreading from previous vaccination [3].
Administration of the UV1 vaccine involves intradermal injection into the patient, with GM-CSF used as an adjuvant to enhance the immune response. The treatment regimen consists of three injections during the first week, followed by booster vaccinations at specific intervals up to 4 years, aimed at mimicking an acute infection or inflammation, followed by maintenance doses [40].
In clinical trials, UV-11 has shown promising results across various cancer types. In a phase I/IIa trial involving men with metastatic hormone-naïve prostate cancer, UV1 combined with GM-CSF induced specific immune responses in a large proportion of patients, resulting in PSA decline and stable disease in a significant number of participants [41]. Similarly, in patients with advanced non-small cell lung cancer (NSCLC), UV1 vaccination demonstrated safety, immune response induction, and favorable long-term clinical outcomes, with median progression-free survival (PFS) and overall survival (OS) reaching notable durations. Notably, higher UV1 dosages correlated with stronger immune responses and improved OS, indicating dose-dependent effects [40].
In metastatic malignant melanoma, UV1 vaccination in combination with ipilimumab, an immune checkpoint inhibitor, showed synergistic effects, with patients exhibiting Th1 immune responses and favorable clinical outcomes, including partial or complete responses and prolonged overall survival. The combination therapy was well-tolerated, suggesting potential benefits of integrating UV1 vaccination with standard treatment regimens containing immune checkpoint inhibitors [42].
Overall, UV1 vaccination has demonstrated safety, efficacy, and immune response induction across multiple cancer types, providing a promising avenue for cancer immunotherapy. The findings from these trials support further investigation of UV1 in combination with existing treatments and its potential integration into standard care protocols for cancer patients. Further research is warranted to explore its utility in larger patient populations and optimize dosing regimens for maximal therapeutic benefit.
Written By: Feng Lin, M.D., Ph.D.
References
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